Atorvastatin (formula I) is manufactured according to published patents (U.S. Pat. Nos. 4,681,893; 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,273,995; 5,397,792; 5,342,952) usually from the sodium salt of (3R,5R) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid and a suitable, water soluble calcium salt, preferably from calcium acetate or chloride.
The starting sodium salt of (3R,5R) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid may be obtained from the said acid, which is normally obtained from (3R,5R) tert-butyl (6-{2-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxane-4-yl)-acetate (formula II).

This key intermediate is converted to the sodium salt of the respective acid first by mixing with hydrochloric acid and, later on, with a large excess of sodium hydroxide, which is, however, accompanied with a large amount of excess hydroxide and also of sodium chloride. Acidification followed by extraction then affords a solution of the respective acid (formula III) without any inorganic impurities. Thus obtained acid is then converted to the respective lactone (formula IV), which can be purified by crystallization, and the purified lactone is then converted to the sodium salt by mixing with an equivalent of sodium hydroxide; an excess cannot be used as it would form, with the calcium salt, calcium hydroxide in the next step that could not be fully removed from the product in the follow up process steps according to the above patents. However, when an equivalent of the hydroxide is used the reaction is time consuming and it has to be monitored by HPLC. Another disadvantage of this process is loss of approximately 20% of the yield.

Depending on the mode of carrying out, atorvastatin is obtained in some of its crystalline forms or as amorphous atorvastatin. In the original patents (for instance U.S. Pat. Nos. 4,681,893 and 5,273,995) there is no mention on the form of the substance obtained under these patents. Later patents (U.S. Pat. Nos. 5,969,156 and 6,121,461), disclosing crystalline forms of atorvastatin, suggest that the substance obtained according to the original patents was amorphous. Patent EP 839,132, disclosing a new method of obtaining the amorphous form of atorvastatin by dissolving crystalline atorvastatin of form I in a non-hydroxylated solvent (the patent mentions tetrahydrofuran and a mixture of tetrahydrofuran and toluene as examples of such solvents) followed by drying, repeats again that the original patents result in amorphous atorvastatin, but that such method is difficult to reproduce. According to our experience, atorvastatin obtained according to previous patents (U.S. Pat. Nos. 4,681,893, 5,298,627 and 5,273,995) is not perfectly amorphous and according to an X-ray analysis it shows the presence of crystalline components (see FIG. 1). The original patent U.S. Pat. No. 4,681,893 also describes a possibility of the purification of the unsuitable substance by dissolving in ethyl acetate, filtration through supercel and precipitation of the solution with hexane at 50° C. A patent to Ranbaxy Laboratories (WO 00/71116 A1) discloses conversion of the crystalline form of atorvastatin in a non-hydroxylated solvent and precipitation of the resulting solution with a non-polar hydrocarbon solvent. A similar approach is described in a patent to Lek (WO 01/42209 A1), which describes conversion of the crystalline form of atorvastatin to the amorphous form by dissolving in a variety of solvents including both non-hydroxylated solvents and lower alcohols, followed by precipitation of these solutions with solvents in which atorvastatin is insoluble. Again, such solvents are broadly defined and, in addition to non-polar hydrocarbon solvents, they include aliphatic ethers.
The objective of this invention is to describe a new improved method of manufacturing an amorphous form of the hemi-calcium salt of (3R,5R) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid that would not show the disadvantages of the above mentioned processes.